The development of the tetracycline antibiotics was the direct result of a systematic screening of soil specimens collected from many parts of the world for evidence of microorganisms capable of producing bactericidal and/or bacteriostatic compositions. The first of these novel compounds was introduced in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. The elucidation of the chemical structure of these compounds confirmed their similarity and furnished the analytical basis for the production of a third member of this group in 1952, tetracycline. A new family of minocycline compounds, without the ring-attached methyl group present in earlier tetracyclines, was prepared in 1957 and became publicly available in 1967; and minocycline was in use by 1972.
Later research efforts have focused on developing new tetracycline antibiotic compositions effective under varying therapeutic conditions and routes of administration. New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced minocycline compounds. Examples include U.S. Pat. Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions.
Historically, soon after their initial development and introduction, the tetracyclines were found to be highly effective pharmacologically against rickettsia; a number of Gram-positive and Gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. Hence, tetracyclines became known as “broad spectrum” antibiotics. With the subsequent establishment of their in vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes.
However, this widespread use of tetracyclines for both major and minor illnesses and diseases led directly to the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic (e.g., pneumococci and Salmonella). The rise of tetracycline-resistant organisms has resulted in a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice. In addition, other antibacterial agents have also been over used, creating strains of multiple drug resistant (MDR) bacteria.
Over the past decade, Gram-positive bacteria with multi-drug resistance to a diverse range of antibiotics have emerged as a major treatment challenge. Two developments raise the specter that currently available antibiotics may become even less useful for treatment of infections caused by Gram-positive organisms. The first is the emergence of vancomycin resistance in Enterococcus species (spp.) and the subsequent transfer of those resistance elements to Staphylococcus aureus. Although vancomycin-resistant Staphylococcus aureus have not become epidemiologically significant, their very existence raises concern because vancomycin has been the agent of choice for infections caused by resistant Gram-positive pathogens.
The second important development is the appearance of community-acquired methicillin-resistant Staphylococcus aureus (MRSA). These strains are increasingly becoming multi-drug resistant over time. In many areas of the world, MRSA infections represent the majority of sporadic staphylococcal infections with community-onset. These strains also have been associated with numerous outbreaks of localized (skin and skin structure) and invasive (bacteremic) infections.
Other than the general need for effective antibacterial agents for the treatment of bacterial infections, there is also a specific need for oral antibiotic therapies.
Compared to IV administration, oral antibiotic therapies can be advantageous because they can eliminate the requirement for hospital visit and/or stay, thus reducing the overall cost of treatment, limiting a patient's exposure to secondary infection in the hospital setting, and increasing the availability of the treatment in areas where hospitals are less accessible or unavailable, particularly in the remote or economically underdeveloped areas or parts of the world.
Unfortunately, due to the rise of antibiotic resistance, use of older agents has led to increasing hospital visits, which in turn increases patients' chances of becoming infected by other bacteria.
Thus there is still a need for a new, effective oral antibacterial agent, particularly oral only dosing regimens, for treating, for example, a bacterial skin or skin structure infection, such as ABSSSI. ABSSSI alone is responsible for more than 750,000 hospitalizations per year (based on the latest data in 2011), representing a 17.3% increase in hospitalized ABSSSI patients from 2005-2011.